TIGIT Expression Is Associated with T-cell Suppression and Exhaustion and Predicts Clinical Outcome and Anti-PD-1 Response in Follicular Lymphoma

Purpose: T-cell immunoglobulin and ITIM domain (TIGIT), a member of the immune checkpoint family, is important in normal T-cell biology. However, the phenotypical profile and clinical relevance of TIGIT in follicular lymphoma is largely unknown. Experimental Design: Biopsy specimens from a cohort of 82 patients with follicular lymphoma were analyzed using mass cytometry to explore the phenotype and biological and clinical significance of TIGIT(+) T cells. Results: TIGIT is highly expressed on intratumoral T cells and its expression alters T-cell phenotype in follicular lymphoma. TIGIT is abundantly expressed on T-reg cells, resulting in an enhanced suppressive property. TIGIT expression on non-T-reg/T-FH T cells defines a population that exhibits an exhausted phenotype. Clinically, increased numbers of TIGIT(+) T cells are associated with inferior patient outcomes and poor survival. We observe that anti-PD-1 therapy with pembrolizumab alters the phenotype of TIGIT(+) T subsets and identifies a role for CD28 expression on TIGIT(+) T cells in treatment response. Conclusions: The current study provides a comprehensive analysis of the phenotypic profile of intratumoral TIGIT(+) T subsets and their prognostic relevance in follicular lymphoma. Inhibition of TIGIT signaling may be an additional mechanism to prevent T-cell suppression and exhaustion in B- cell lymphoma.